Comparison between beta‐blockers and calcium channel blockers in patients with atrial fibrillation according to renal function

Abstract Background Rate control is the most commonly employed first‐line management strategy for atrial fibrillation (AF) in patients with chronic kidney disease (CKD). Principal agents used to control heart rate (HR) include beta‐blockers (BB) and nondihydropyridine calcium channel blockers (ND‐CCB). However, there is a paucity of published studies of the differences between those drugs in CKD patients. Hypothesis The present study aimed to investigate the differences, in terms of hospitalizations due to a poor HR control, in patients with AF under a rate‐control strategy according to glomerular filtration rate (GFR). Methods The study cohort included 2804 AF patients under rate‐control regime (BB or ND‐CCB) between January 2014 and April 2020. The end point, determined by competing risk regression, was hospitalizations for AF with rapid ventricular response (RVR), slow ventricular response (SVR), and need for pacemaker. Results On multivariate analysis, there were no statistical differences between ND‐CCB and BB for subjects with GFR > 60 mL/min/1.73 m2 (subdistribution heart rate [sHR] 0.850, 95% confidence interval [CI]: 0.61–1.19; p = .442) and GFR 30–59 mL/min/1.73 m2 (sHR 1.242, 95% CI: 0.80–1.63; p = .333), while in patients with GFR < 30 mL/min/1.73 m2, ND‐CCB therapy was associated with increased hospitalizations due to poor HR control (sHR 4.53, 95% CI: 1.19–17.18; p = .026). Conclusion In patients with GFR ≥ 30 mL/min/1.73 m2, the choice of ND‐CCB or BB had no impact on hospitalizations due to poor HR control, while in GFR < 30 mL/min/1.73 m2, a possible association was detected. The effects of these drugs on GFR < 30 mL/min/1.73 m2 would require further investigation.


| INTRODUCTION
Atrial fibrillation (AF) and chronic kidney disease (CKD) frequently coexist, as both share risk factors and pathophysiologic mechanisms. 1 Patients with CKD have a threefold increased risk of AF compared with the healthy population. 2 In fact, recent registry data suggest that there is a close bidirectional relationship between both conditions. 3art rate (HR) control is the most commonly employed first-line management strategy for AF in patients with CKD. 4 Excessive ventricular rates during AF might cause severe symptoms, such as palpitations, dyspnea and fatigue.Even, in some patients, it can lead to the development of a tachycardia-induced cardiomyopathy and may worsen congestive heart failure (HF), increasing the risk of hospital admission and mortality. 5rategies targeted at reducing the ventricular rate during AF rely on agents that work by prolonging atrioventricular node refractoriness.Principal classes of agents used include beta-adrenergic blockers (BB) and nondihydropyridine calcium channel blockers (ND-CCB).There is little evidence to support selection of HR control therapy in patients with AF, in particular those with coexisting CKD.
Despite the high prevalence of AF in patients with CKD, there is a paucity of published studies of the clinical value and differences between those drugs in this context.Furthermore, CKD patients are commonly underprescribed recommended cardiovascular medications. 6e present study aimed to investigate the differences, in terms of hospitalizations due to a poor HR control, in patients with AF under a rate-control strategy according to glomerular filtration rate (GFR).below 40% (n = 1476) were excluded from this analysis; we also excluded 6273 patients under a rhythm-control strategy and 3975 subjects who were not taking any treatment (nor rhythm-control nor rate-control).Thereby, the final study group consisted of 2804 patients (Figure 1).The entire data handling process complied with ethical and legal standards, in particular with Declaration of Helsinki and was approved by the local ethics committee.All the data were collected and processed and were anonymized by a code.Informed consent was not required for the present study.

| Follow-up, definition, and study outcomes
Follow-up was performed from the first time the patient was medically assessed for AF between January 2014 and April 2020 and lasted until September 2020.Patients remained in the analysis until an event occurred or until the end of follow-up.
The end point of the study was admissions due to poor heart rate control, defined as hospitalizations for AF with RVR, hospitalizations for AF with SVR, and need for pacemaker.

| Statistical analysis
Baseline characteristics were described using frequencies and percentages for categorical data, and mean ± standard deviation for

Key points
• Rate control is the most commonly employed first-line management strategy for atrial fibrillation in patients with chronic kidney disease.Evidence to guide selection between beta-blockers and nondihydropyridine calcium channel blockers is scarce.
• This is the first study to compare patients with atrial fibrillation under rate-control strategy according to renal function.
• In patients with glomerular filtration rate (GFR) ≥ 30 mL/ min/1.73m 2 , both nondihydropyridine calcium channel blockers (ND-CCB) and beta-blockers therapy have good results in heart rate (HR) control, while in advanced chronic kidney disease (GFR < 30 mL/min/1.73m 2 ), a possible association of ND-CCB with increased hospitalizations due to poor HR control was detected.continuous data.Differences in characteristics were determined using χ 2 tests and unpaired t tests, respectively.Normality was analyzed with Shapiro-Wilk test.The risk of admissions due to a poor HR control was determined by competing risk regression using the fine and gray model, considering death as a competing risk.Fine and gray models were fitted by GFR.Multivariate adjustment was developed including all those variables with clinical significance and those that had been associated with higher risk of the combined end point of in the univariate analysis (Supporting Information S1: Table 1).
Results were reported as subdistribution HR (sHR) and 95% confidence interval (CI) and were graphically represented with cumulative incidence curves.All p values < .05were accepted as statistically significant.All statistical analyses were performed using Stata 16.1.

| RESULTS
A total of 2804 patients (82.0 ± 4.8 years, 62.2% women) were followed up.The baseline characteristics are presented in Table 1.
Patients under BB tend to be older (82 vs. 80 years, p = .000)and had more hypertension than those treated with ND-CCB.The use of anticoagulation therapy was comparable between both groups (BB 86.2% vs. ND-CCB 85.8%).
The incidence of hospitalizations increased among patients who received ND-CCB as baseline GFR declined (Figure 2).AF without heart failure. 13As well as in the RACE II trial, patients included in the RATAF study were relatively young (71 ± 9 years), had low comorbidity burden and no data regarding to GFR have been shown.Both diltiazem, which seemed to be the most effective in reducing the ventricular rate, and verapamil, preserved exercise capacity, reduced arrhythmia-related symptoms, and reduced levels of NT-pro-B-natriuretic peptide, but not BB.Those positive effects of ND-CCB and the fact that recent studies have suggested that BB use in both HFpEF and AF may increase the risk for HF, 14 had led Meyer et al. to conduct a large retrospective cohort analysis, comparing ND-CCB and BB in patients with AF and heart failure, with controversial results. 15mpared with BB, ND-CCB were associated with fewer HF admissions but also with more all-cause deaths.No subgroup analysis according to GFR has been made in this study.
Randomized studies that compare the two medication classes have not been performed yet.While the pharmacokinetics of ND-CCB is unaltered in patients with CKD, 16 BB are renally or hepatically cleared depending on the type. 17Even, ND-CCB have been shown to possess an antiproteinuric effect that could be ND-CCB as the first choice in CKD, a result which is higher than the registered in our cohort. 18te control may result in slow ventricular rates or heart block.In the RACE II trial, the need for pacemaker was 1.4% at 3 years in the strict rate-control arm (similar to the 0.8% observed in the lenient ratecontrol arm), despite the possibility to combine BB plus ND-CCB (used in more than one-fifth of the patients).It has been reported that in patients with CKD, major ECG abnormalities are frequently present. 19r cohort included older patients than the RACE II trial, with a bigger burden of comorbidities and almost 52% of them had CKD, which could explain the higher implantation rate of pacemaker (2.57%).Even so, the implantation rate of pacemakers in this cohort was low.
The possible association of ND-CCB with increased hospitalization due to poor HR control in patients with advanced CKD is underpowered and it should be endorsed in other studies.

| Limitations
There are some limitations inherent to the retrospective study design and the subsequent bias.The two patient groups (BB and ND-CCB) were of unequal size.Outcomes were analyzed according to treatment at baseline and treatment changes were not accounted for in this study.Furthermore, there was a lack of details (e.g., dose and type) on the prescription of ND-CCB and BB (despite the fact that the most common BB in our area is bisoprolol, we do not have data in this cohort).
T A B L E 2 Subhazard ratios for the risk of hospitalizations due to poor heart rhythm control (admissions for AF with RVR, AF with SVR, and need for pacemaker).
This is a retrospective observational study conducted in a subset of participants treated with BB or ND-CCB of the CardioCHUVI-AF registry (Registry of Atrial Fibrillation from University Hospital of Vigo, NCT-04364516).AF patients were identified through administrative databases, using the Galician Healthcare Service information system.Electronic medical records were analyzed to collect data on baseline clinical variables, treatment, and follow-up events.Pharmacotherapy was determined by means of filled prescriptions.The CardioCHUVI-AF registry included 16,056 patients from the health area of Vigo (Galicia, Spain) with a confirmed diagnosis based on an electrocardiogram between January 2014 and April 2020.Patients without data regarding to GFR (n = 208), those who received digoxin (n = 1304) and those with left ventricular ejection fraction (LVEF)
12e evidence on rate control in AF management is limited.ESC guidelines include a Class II recommendation for lenient rate control (<110 bpm) in asymptomatic patients with AF,11based on the results of the RACE II trial, which showed that a lenient rate-control treatment strategy (<110 bpm) was noninferior to a strict rate-control treatment strategy (<80 bpm) in terms of symptoms control and mortality.12Nodrug-specific subanalysis had been performed.To evaluate the efficacy between BB and ND-CCB, Ulimoen et al. promoted the Rate Control in Atrial Fibrilla (RATAF) study, which compared four rate-controlling drugs (BB and ND-CCB) in only 60 symptomatic patients with permanent Incidence of hospitalizations due to poor heart rate control in patients with AF according to glomerular filtration rate.AF, atrial fibrillation.